Novel imine derivative compound and use thereof

Abstract

The present invention relates to a novel imine derivative compound and a use thereof. The compound of the present invention can contribute to cancer immunotherapy by inhibiting a target protein involved in the Trp-Kyn conversion mechanism so as to induce the death of cancer cells, and thus can be used for preventing or treating cancer diseases.

Description

Novel imine derivative compounds and uses thereof

[0001] The present invention relates to a novel imine derivative compound and its use.

[0002] Unlike conventional cancer drugs that attack the cancer itself, immunotherapy drugs are drugs that stimulate the immune system by injecting artificial immune proteins into the body, causing immune cells to selectively attack only cancer cells. The first immunotherapy drug was Provenge®, an autologous tumor vaccine, which was approved by the US FDA in 2010 for the treatment of prostate cancer. Yervoy®, a CTLA4 inhibitor and the first immune checkpoint inhibitor, was approved by the US FDA in 2011 and in Korea in 2014 for the treatment of metastatic melanoma. With the advent of these first-generation immunotherapy drugs, the main paradigm of cancer treatment shifted to immunotherapy, and subsequently, second-generation immunotherapy drugs, anti-PD1 / PD-L1 antibodies, which have higher overall survival rates than existing treatments, were developed.

[0003] Immunotherapy can be divided into passive immunotherapy and active immunotherapy. Passive immunotherapy includes immune checkpoint inhibitors, immune cell therapy, and therapeutic antibodies, while active immunotherapy includes anticancer vaccines and immune-modulating agents.

[0004] The body's immune function regulates overall T cell function by regulating these co-stimulatory and co-inhibitory signals simultaneously with antigen recognition. Immune cells detect tumor-specific antigens expressed due to changes such as mutations that occur in cancer cells and eliminate cancer cells. However, cancer cells try to evade immune attacks by altering the tumor microenvironment to suppress immune function or through T cell immune tolerance or immune-editing to achieve immune escape. One of these evasion strategies is to suppress T cell function by changing the function of immune checkpoints. In other words, immune checkpoints are proteins that interfere with the destruction of cancer cells, and cancers avoid T cell attacks by activating inhibitory immune checkpoints. Unlike existing immunotherapeutic agents (cytokine therapy, anticancer vaccines, etc.), immune checkpoint inhibitors have a mechanism in which they bind to the junction between cancer cells and T cells to block immune evasion signals, thereby preventing the formation of immunological synapses and allowing T cells that are not immune evasion interference to destroy cancer cells. Immune checkpoint inhibitors include CTLA-4, PD-1, and PD-L1 inhibitors.

[0005] However, while immune checkpoint inhibitor monotherapy can lead to long-term survival in some patients, it has significant limitations: approximately 40-70% of patients do not respond. To overcome these limitations, various studies have recently been conducted, including the combination of anti-PD1 / PD-L1 antibodies with existing anticancer therapies. Combination therapies with various anticancer mechanisms are currently in clinical trials. These combination therapies require maximizing synergy with existing immune checkpoint inhibitors without overlapping anticancer mechanisms, and blocking immunosuppressive pathways is essential.

[0006] The tumor microenvironment is a cellular environment surrounding cancer cells, including blood vessels, immune cells, fibroblasts, bone marrow-derived inflammatory cells, lymphocytes, signaling molecules, and extracellular matrix. In the tumor microenvironment, cancer cells affect the microenvironment by releasing extracellular signals, promoting cancer cell angiogenesis, and inducing peripheral immune tolerance. Cancer cells can change the microenvironment, and the microenvironment can affect the growth or metastasis of cancer cells. The enzymes IDO1, IDO2, and TDO are enzymes that form kynurenine (Kyn) from tryptophan (Trp). When overexpressed, they deplete tryptophan and create an immunosuppressive environment. This is done through various mechanisms. eff Inhibition and T reg In addition to inducing activation, kynurenine acts as an endogenous ligand of the aryl hydrocarbon receptor (AhR), thereby inducing tumor malignancy, thereby creating a tumor / immune cell microenvironment that suppresses the immune system from attacking cancer cells and inducing immune tolerance.

[0007] Accordingly, the inventor of the present invention completed the present invention by developing a direct inhibitor for a target protein involved in the Trp-Kyn conversion mechanism while conducting research to develop a small molecule agent for tumor microenvironment-specific metabolic regulation that can contribute to immunotherapy of cancer.

[0008] The purpose of the present invention is to provide a novel imine derivative compound and an anticancer pharmaceutical composition comprising the same as an active ingredient.

[0009] To achieve the above purpose, the present invention provides a compound represented by the following chemical formula 1, a stereoisomer thereof, a tautomer, a derivative, a hydrate, a solvate thereof, or a pharmaceutically acceptable salt thereof.

[0010] Chemical Formula 1

[0011]

[0012] {In the above chemical formula 1,

[0013] X is O or S,

[0014] L is C1~C 30 alkylene group; C2~C 30 alkenylene group of; or C2~C 30 is selected from the group consisting of alkynylene groups;

[0015] Ar 1 and Ar 2 are independently C6~C 30 Aryl group of; C2~C containing at least one heteroatom of N, O or S 30 Heterocyclic group of; and C3~C 30 is selected from the group consisting of aliphatic rings;

[0016] Here, the above alkyl group, alkenyl group, alkynyl group, aryl group, heterocyclic group and aliphatic ring group are each halogen; cyano group; hydroxy group; nitro group; amino group; acetoxy group; C1~C 20 Alkyl group of; C2~C 20 Alkenyl group of; C2~C 20 Alkynyl group of; C1~C 20 Alkoxy group of; C6~C 20 Aryl group of; C6~C 20 Aryloxy group of; C7~C 20 Arylalkyl group of; C1~C 20 Alkyl ester group of; C2~C containing at least one heteroatom of N, O or S 20 Heterocyclic group of; and C3~C 20 may be further substituted with one or more substituents selected from the group consisting of an aliphatic ring group;

[0017] The above L is C1~C 30 It is characterized by an alkylene group.

[0018] The above Ar 1 and Ar 2 are independently of each other C1~C 20 C6~C substituted or unsubstituted with an alkyl group 30It is characterized by being an aryl group.

[0019] The above chemical formula 1 is characterized by being represented by the following chemical formula 1-1 or chemical formula 1-2.

[0020] Chemical Formula 1-1 Chemical Formula 1-2

[0021]

[0022] {In the above chemical formula 1-1 and chemical formula 1-2, X, L, Ar 1 and Ar 2 is the same as defined above.}

[0023] The above chemical formula 1 is characterized by being represented by the following chemical formula 1-3.

[0024] Chemical Formula 1-3

[0025]

[0026] {In the above chemical formula 1-3,

[0027] X, L and Ar 2 is the same as defined above,

[0028] R 1 are independently the same or different from each other, hydrogen; deuterium; halogen; cyano group; hydroxyl group; nitro group; amino group; acetoxy group; C1~C 20 Alkyl group of; C2~C 20 Alkenyl group of; C2~C 20 Alkynyl group of; C1~C 20 Alkoxy group of; C6~C 20 Aryl group of; C6~C 20 Aryloxy group of; C7~C 20 Arylalkyl group of; C1~C 20 Alkyl ester group of; C2~C containing at least one heteroatom of N, O or S 20 Heterocyclic group of; and C3~C 20 is selected from the group consisting of aliphatic rings;

[0029] a is an integer from 0 to 5.}

[0030] The above chemical formula 1 is characterized by being represented by the following chemical formula 1-4.

[0031] Chemical Formula 1-4

[0032]

[0033] {In the above chemical formula 1-4,

[0034] X and Ar 1 is the same as defined above,

[0035] R 2 are independently the same or different from each other, hydrogen; deuterium; halogen; cyano group; hydroxyl group; nitro group; amino group; acetoxy group; C1~C 20 Alkyl group of; C2~C 20 Alkenyl group of; C2~C 20 Alkynyl group of; C1~C 20 Alkoxy group of; C6~C 20 Aryl group of; C6~C 20 Aryloxy group of; C7~C 20 Arylalkyl group of; C1~C 20 Alkyl ester group of; C2~C containing at least one heteroatom of N, O or S 20 Heterocyclic group of; and C3~C 20 is selected from the group consisting of aliphatic rings;

[0036] R 3 is hydrogen; or C6~C 20 aryl group of;

[0037] b is an integer from 0 to 5.}

[0038] The above chemical formula 1 is characterized by being represented by the following chemical formula 1-5.

[0039] Chemical Formula 1-5

[0040]

[0041] {In the above chemical formula 1-5,

[0042] X is as defined above,

[0043] R 1 and R 2 are independently the same or different from each other, and independently hydrogen; deuterium; halogen; cyano group; hydroxyl group; nitro group; amino group; acetoxy group; C1~C 20 Alkyl group of; C2~C 20 Alkenyl group of; C2~C 20 Alkynyl group of; C1~C 20 Alkoxy group of; C6~C 20 Aryl group of; C6~C 20 Aryloxy group of; C7~C 20 Arylalkyl group of; C1~C 20 Alkyl ester group of; C2~C containing at least one heteroatom of N, O or S 20 Heterocyclic group of; and C3~C 20 is selected from the group consisting of aliphatic rings;

[0044] R 3 is hydrogen; or C6~C 20 aryl group of;

[0045] a and b are integers from 0 to 5, independently of each other.

[0046] In addition, in another aspect, the present invention provides an anticancer pharmaceutical composition comprising a compound represented by the above chemical formula 1, a stereoisomer, a tautomer, a derivative, a hydrate, a solvate or a pharmaceutically acceptable salt thereof as an active ingredient.

[0047] The composition is used for the treatment of brain cancer, neuroendocrine cancer, myeloma, lymphoma, leukemia, lymphangioendotheliosarcoma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, glioma, meningioma, neuroblastoma, EMC (extraskeletal myxoid chondrosarcoma), stomach cancer, lung cancer, breast cancer, ovarian cancer, liver cancer, bronchial cancer, nasopharyngeal cancer, laryngeal cancer, pancreatic cancer, bladder cancer, adrenal cancer, colon cancer, colon cancer, cervical cancer, prostate cancer, bone cancer, skin cancer, thyroid cancer, parathyroid cancer, ureter cancer, testicular tumor, lung carcinoma, small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, colon adenocarcinoma, prostate carcinoma, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, renal cell carcinoma, It is characterized by having as the target disease at least one selected from the group consisting of hepatocellular carcinoma, biliary tract cancer, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteosarcoma, chordoma, hemangiosarcoma, endotheliosarcoma, lymphangiosarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, rhabdomyosarcoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, bulbar thyroid carcinoma, bronchial carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilm's tumor, Kaposi sarcoma, and retinoblastoma.

[0048] The above composition is characterized by inducing apoptosis of cancer cells through inhibition of indoleamine 2,3-dioxygenase 1 (IDO1) or indoleamine 2,3-dioxygenase 2 (IDO2).

[0049] In another aspect, the present invention provides a method of treating cancer in a non-human animal comprising administering the composition.

[0050] The compound according to the present invention can contribute to immunotherapy by inhibiting target proteins IDO1 or IDO2 involved in the Trp-Kyn conversion mechanism and thereby inducing apoptosis of cancer cells, and can be used for the prevention or treatment of cancer diseases.

[0051] Hereinafter, the present invention will be described in detail with reference to embodiments. In describing the present invention, if a detailed description of a related known configuration or function is judged to obscure the gist of the present invention, such detailed description will be omitted.

[0052] As used in this specification and the appended claims, unless otherwise stated, the following terms have the following meanings:

[0053] The term "halogen" as used in the present invention is fluorine (F), bromine (Br), chlorine (Cl), or iodine (I) unless otherwise stated.

[0054] The term "alkyl" or "alkyl group" as used in the present invention means an aliphatic hydrocarbon radical, and refers to a radical of a saturated aliphatic functional group including a straight-chain alkyl group, a branched-chain alkyl group, a cycloalkyl (alicyclic) group, an alkyl-substituted cycloalkyl group, and a cycloalkyl-substituted alkyl group. For example, C1~C6 alkyl is an aliphatic hydrocarbon having 1 to 6 carbon atoms, and includes methyl, ethyl, propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, neopentyl, isopentyl, and the like.

[0055] The term "alkenyl group" or "alkynyl group" as used in the present invention means a group in which at least two carbon atoms are formed by at least one carbon-carbon double bond or at least two carbon atoms are formed by at least one carbon-carbon triple bond, and includes, but is not limited to, straight-chain or branched-chain groups.

[0056] The term "alkoxy group" or "alkoxy group" used in the present invention, unless otherwise defined, means a radical in which a hydrogen atom of a hydroxy group is replaced with an alkyl, and for example, alkoxy having C1 to C6 includes methoxy, ethoxy, propoxy, n-butoxy, n-pentyloxy, isopropoxy, sec-butoxy, tert-butoxy, neopentyloxy, isopentyloxy, etc.

[0057] The term "heterocycle" or "heterocyclic group" as used in the present invention includes, unless otherwise specified, a compound containing one or more heteroatoms or heteroatom groups such as SO2, and includes at least one of a single ring and a multi-ring, and includes a heteroaliphatic ring and a heteroaromatic ring. It may also be formed by bonding adjacent functional groups.

[0058] The term "aryl group" or "arylene group" as used in the present invention refers to a single-ring or multi-ring aromatic group, and includes an aromatic ring formed by the bonding or reaction of adjacent substituents. For example, the aryl group may be a phenyl group, a biphenyl group, a fluorene group, or a spirofluorene group.

[0059] The term “aliphatic ring” used in the present invention means an aliphatic hydrocarbon ring.

[0060] The term "aromatic ring" used in the present invention means an aromatic system composed of hydrocarbons containing one or more rings, examples of which include benzene, naphthalene, etc.

[0061] Additionally, the definitions described herein can be added to form chemically related combinations, such as "arylalkyl," "alkylcarbonyl," "arylcarbonyl," etc. The term "alkyl" when used as a suffix, such as in another term below, "phenylalkyl" or "hydroxyalkyl," means an alkyl group substituted with a substituent selected from another clearly named group. Thus, for example, "phenylalkyl" means an alkyl group having a phenyl substituent, and thus includes benzyl, phenylethyl, and biphenyl. "Alkylaminoalkyl" means an alkyl group having an alkylamino substituent.

[0062] Hereinafter, a compound according to one aspect of the present invention and an anticancer pharmaceutical composition comprising the same will be described.

[0063] The present invention provides a compound represented by the following chemical formula 1, a stereoisomer, a tautomer, a derivative, a hydrate, a solvate or a pharmaceutically acceptable salt thereof.

[0064] Chemical Formula 1

[0065]

[0066] {In the above chemical formula 1,

[0067] X is O or S,

[0068] L is C1~C 30 alkylene group; C2~C 30 alkenylene group of; or C2~C 30 is selected from the group consisting of alkynylene groups;

[0069] Ar 1 and Ar 2 are independently C6~C 30 Aryl group of; C2~C containing at least one heteroatom of N, O or S 30 Heterocyclic group of; and C3~C 30 is selected from the group consisting of aliphatic rings;

[0070] Here, the above alkyl group, alkenyl group, alkynyl group, aryl group, heterocyclic group and aliphatic ring group are each halogen; cyano group; hydroxy group; nitro group; amino group; acetoxy group; C1~C 20 Alkyl group of; C2~C 20 Alkenyl group of; C2~C 20 Alkynyl group of; C1~C 20 Alkoxy group of; C6~C 20 Aryl group of; C6~C 20 Aryloxy group of; C7~C 20 Arylalkyl group of; C1~C 20 Alkyl ester group of; C2~C containing at least one heteroatom of N, O or S 20 Heterocyclic group of; and C3~C 20 may be further substituted with one or more substituents selected from the group consisting of an aliphatic ring group;

[0071] In addition, the present invention is characterized in that the L is C1~C 30 Provided is a compound having an alkylene group, a stereoisomer, a tautomer, a derivative, a hydrate, a solvate or a pharmaceutically acceptable salt thereof.

[0072] The above Ar 1 and Ar 2 are independently of each other C1~C 20 C6~C substituted or unsubstituted with an alkyl group 30 Provided is a compound, a stereoisomer, a tautomer, a derivative, a hydrate, a solvate or a pharmaceutically acceptable salt thereof, which is an aryl group.

[0073] For example, the chemical formula 1 may be represented by the following chemical formula 1-1 or chemical formula 1-2.

[0074] Chemical Formula 1-1 Chemical Formula 1-2

[0075]

[0076] {In the above chemical formula 1-1 and chemical formula 1-2, X, L, Ar 1 and Ar 2is the same as defined above.}

[0077] For example, the above chemical formula 1 can be represented by the following chemical formula 1-3.

[0078] Chemical Formula 1-3

[0079]

[0080] {In the above chemical formula 1-3,

[0081] X, L and Ar 2 is the same as defined above,

[0082] R 1 are independently the same or different from each other, hydrogen; deuterium; halogen; cyano group; hydroxyl group; nitro group; amino group; acetoxy group; C1~C 20 Alkyl group of; C2~C 20 Alkenyl group of; C2~C 20 Alkynyl group of; C1~C 20 Alkoxy group of; C6~C 20 Aryl group of; C6~C 20 Aryloxy group of; C7~C 20 Arylalkyl group of; C1~C 20 Alkyl ester group of; C2~C containing at least one heteroatom of N, O or S 20 Heterocyclic group of; and C3~C 20 is selected from the group consisting of aliphatic rings;

[0083] a is an integer from 0 to 5.}

[0084] For example, the above chemical formula 1 can be represented by the following chemical formula 1-4.

[0085] Chemical Formula 1-4

[0086]

[0087] {In the above chemical formula 1-4,

[0088] X and Ar 1 is the same as defined above,

[0089] R2 are independently the same or different from each other, hydrogen; deuterium; halogen; cyano group; hydroxyl group; nitro group; amino group; acetoxy group; C1~C 20 Alkyl group of; C2~C 20 Alkenyl group of; C2~C 20 Alkynyl group of; C1~C 20 Alkoxy group of; C6~C 20 Aryl group of; C6~C 20 Aryloxy group of; C7~C 20 Arylalkyl group of; C1~C 20 Alkyl ester group of; C2~C containing at least one heteroatom of N, O or S 20 Heterocyclic group of; and C3~C 20 is selected from the group consisting of aliphatic rings;

[0090] R 3 is hydrogen; or C6~C 20 aryl group of;

[0091] b is an integer from 0 to 5.}

[0092] For example, the above chemical formula 1 can be represented by the following chemical formula 1-5.

[0093] Chemical Formula 1-5

[0094]

[0095] {In the above chemical formula 1-5,

[0096] X is as defined above,

[0097] R 1 and R 2 are independently the same or different from each other, and independently hydrogen; deuterium; halogen; cyano group; hydroxyl group; nitro group; amino group; acetoxy group; C1~C 20 Alkyl group of; C2~C 20 Alkenyl group of; C2~C 20 Alkynyl group of; C1~C 20 Alkoxy group of; C6~C 20 Aryl group of; C6~C20 Aryloxy group of; C7~C 20 Arylalkyl group of; C1~C 20 Alkyl ester group of; C2~C containing at least one heteroatom of N, O or S 20 Heterocyclic group of; and C3~C 20 is selected from the group consisting of aliphatic rings;

[0098] R 3 is hydrogen; or C6~C 20 aryl group of;

[0099] a and b are integers from 0 to 5, independently of each other.

[0100] Specifically, the above chemical formula 1 may be represented by any one of the following compounds, but is not limited thereto.

[0101]

[0102]

[0103]

[0104]

[0105]

[0106] The compound according to the present invention can induce cancer cell death through tumor microenvironment-specific metabolic regulation that can contribute to immunotherapy, and more specifically, can induce cancer cell death through direct inhibition of a target protein involved in the tryptophan-kynurenine conversion mechanism. The target protein includes indoleamine 2,3-dioxygenase 1 (IDO1) or indoleamine 2,3-dioxygenase 2 (IDO2).

[0107] In addition, in another aspect, the present invention provides an anticancer pharmaceutical composition comprising a compound represented by the above chemical formula 1, a stereoisomer, a tautomer, a derivative, a hydrate, a solvate or a pharmaceutically acceptable salt thereof as an active ingredient.

[0108] The composition is used for the treatment of brain cancer, neuroendocrine cancer, myeloma, lymphoma, leukemia, lymphangioendotheliosarcoma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, glioma, meningioma, neuroblastoma, EMC (extraskeletal myxoid chondrosarcoma), stomach cancer, lung cancer, breast cancer, ovarian cancer, liver cancer, bronchial cancer, nasopharyngeal cancer, laryngeal cancer, pancreatic cancer, bladder cancer, adrenal cancer, colon cancer, colon cancer, cervical cancer, prostate cancer, bone cancer, skin cancer, thyroid cancer, parathyroid cancer, ureter cancer, testicular tumor, lung carcinoma, small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, colon adenocarcinoma, prostate carcinoma, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, renal cell carcinoma, The target disease may be at least one selected from the group consisting of hepatocellular carcinoma, biliary tract cancer, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteosarcoma, chordoma, hemangiosarcoma, endotheliosarcoma, lymphangiosarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, rhabdomyosarcoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, bulbar thyroid carcinoma, bronchial carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilm's tumor, Kaposi sarcoma, and retinoblastoma, but is not limited thereto.

[0109] The above composition can induce apoptosis of cancer cells through inhibition of indoleamine 2,3-dioxygenase 1 (IDO1) or indoleamine 2,3-dioxygenase 2 (IDO2).

[0110] In another aspect, the present invention provides a method of treating cancer in a non-human animal comprising administering the composition.

[0111] In addition, in the present invention, the composition may include a pharmaceutically acceptable carrier or a pharmaceutically acceptable excipient in addition to the imine derivative compound. Specifically, the carrier is one commonly used in formulations, and may be, but is not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methylcellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, or mineral oil. Excipients such as cocoa butter and suppository wax, coloring agents, coating agents, sweeteners, flavoring agents, and fragrances may also be present in the composition.

[0112] The excipients include any and all solvents, inert diluents, dispersing and / or granulating agents, surface active and / or emulsifying agents, disintegrating agents, binders, preservatives, buffers, lubricants and / or oils suitable for the particular dosage form desired. Excipients such as cocoa butter and suppository wax, coloring agents, coating agents, sweetening agents, flavoring agents and perfuming agents may also be present in the composition.

[0113] Exemplary diluents include, but are not limited to, calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate, lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, corn starch, powdered sugar, and combinations thereof.

[0114] Exemplary preservatives include, but are not limited to, antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, alcohol preservatives, acid preservatives, and other preservatives.

[0115] Exemplary antioxidants include, but are not limited to, alpha tocopherol, ascorbic acid, acorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium iodide, sodium metabisulfite, sodium nitrite, sodium sulfite, and sodium thiosulfate.

[0116] Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) and its salts and hydrates (e.g., sodium edetate, disodium edetate, trisodium edetate, disodium calcium edetate, dipotassium edetate, etc.), citric acid and its salts and hydrates (e.g., citric acid monohydrate), fumaric acid and its salts and hydrates, malic acid and its salts and hydrates, phosphoric acid and its salts and hydrates, and tartaric acid and its salts and hydrates. Exemplary antimicrobial preservatives include, but are not limited to, benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal.

[0117] Exemplary antifungal preservatives include, but are not limited to, butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid.

[0118] Exemplary alcohol preservatives include, but are not limited to, ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenols, chlorobutanol, hydroxybenzoates, and phenylethyl alcohol.

[0119] Exemplary acidic preservatives include, but are not limited to, vitamin A, vitamin C, vitamin E, beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid.

[0120] Other preservatives include, but are not limited to, tocopherol, tocopherol acetate, deteroxime mesylate, cetrimide, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, Glydant Plus, Phenonip, methylparaben, Germall 115, Germaben II, Neolone, Kathon, and Euxyl.

[0121] Exemplary buffers include citrate buffer solution, acetate buffer solution, phosphate buffer solution, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium globionate, calcium glucept, calcium gluconate, D-gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxide, potassium acetate, potassium chloride, potassium gluconate, potassium mixture, dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixture, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, sodium phosphate mixture, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, and the like, and combinations thereof, are included but are not limited thereto.

[0122] The composition of the present invention may be administered orally or parenterally. In the case of parenteral administration, it may be administered parenterally by intravenous injection, intraarterial injection, subcutaneous injection, intramuscular injection, intra-articular injection, intrasynovial injection, intrathecal injection, intrahepatic injection, intralesional injection, intracranial injection, or topically. Specifically, the composition of the present invention may be formulated as an injection and administered intravenously, but is not limited thereto.

[0123] In addition, the composition may take various forms, including, but not limited to, a liquid, suspension, paste, powder, concentrate, granulated powder for mixing to an appropriate concentration, or a solid form, each according to a conventional method. For example, the composition of the present invention may be prepared in the form of an injection, a preparation for transdermal administration, a preparation for intubation, a preparation for oral administration, or a preparation for rectal administration.

[0124] The appropriate dosage of the composition of the present invention can be prescribed in various ways depending on factors such as the formulation method, administration method, patient's age, weight, sex, pathological condition, food, administration time, administration route, excretion rate, and response sensitivity.

[0125]

[0126] Hereinafter, examples of synthesis and examples of the compound represented by the chemical formula 1 of the present invention will be described in detail with reference to examples, but the present invention is not limited to the following examples.

[0127] [Synthesis example]

[0128] (Z)-N-(2,2-diphenylethyl)-N'-phenylfuran-2-carboximidamide (K15)

[0129] A solution of N-phenylfuran-2-carboxamide (200 mg, 1.07 mmol) in SOCl2 (2 mL) was stirred at 80°C for 6 h. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was dissolved in toluene (2 mL), and the mixture was evaporated again. 2,2-diphenylethylamine (362 mg, 2.14 mmol) and TEA (0.444 mL, 3.21 mmol) were mixed in DCM (4 mL), and the evaporated solution was added. The mixture was stirred at 0°C for 5 min and heated at 50°C for 2 h. After cooling to room temperature, the reaction mixture was extracted with ethyl acetate and washed with brine. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography to give the product (191 mg, 49%).

[0130] R f (n-hexane / EtOAc, 90:10) = 0.38; yellow oil.

[0131] 1 H NMR (300 MHz, CDCl3): 7.56 (d, J = 1.8 Hz, 1H), 7.37 - 7.15 (m, 12H), 7.00 - 6.86 (m, 2H), 6.65 - 6.55 (m, 2H), 6.34 (dd, J = 3.5, 1.8 Hz, 1H), 5.73 (s, 1H), 4.58 (d, J = 7.8 Hz, 1H), 4.04 - 3.89 (m, 2H). - 13C NMR (101 MHz, DMSO): 152.42, 145.98, 143.64, 143.49, 129.18, 128.84, 128.54, 126.72, 121.69, 121.63, 113.94, 111.66, 49.82, 45.40.

[0132]

[0133] (Z)-N-phenethyl-N'-phenylfuran-2-carboximidamide (K19)

[0134] A solution of N-phenylfuran-2-carboxamide (200 mg, 1.07 mmol) in SOCl2 (2 mL) was stirred at 80°C for 6 h. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was dissolved in toluene (2 mL), and the mixture was evaporated again. Phenethylamine (0.270 mL, 2.14 mmol) and TEA (0.444 mL, 3.21 mmol) were mixed in DCM (4 mL), and the evaporated solution was added. The mixture was stirred at 0°C for 5 min and heated at 50°C for 2 h. After cooling to room temperature, the reaction mixture was extracted with ethyl acetate and washed with brine. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography to give the product (232 mg, 75%).

[0135] R f (n-hexane / EtOAc, 80:20) = 0.55; yellow oil.

[0136] 1 H NMR (300 MHz, CDCl3): 7.38 - 7.19 (m, 9H), 7.08 - 6.96 (m, 1H), 6.88 - 6.77 (m, 2H), 6.29 - 6.13 (m, 1H), 5.63 (s, 1H), 5.40 (s, 1H), 3.74 (t, J = 6.9 Hz, 2H), 3.00 (t, J = 6.9 Hz, 2H).

[0137]

[0138] (Z)-N-(2,2-diphenylethyl)-N'-(p-tolyl)furan-2-carboximidamide (K23)

[0139] A solution of N-(p-toyl)furan-2-carboxamide (200 mg, 0.995 mmol) in SOCl2 (2 mL) was stirred at 80°C for 6 h. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was dissolved in toluene (2 mL), and the mixture was evaporated again. Phenylethylamine (392 mg, 1.99 mmol) and TEA (0.414 mL, 2.98 mmol) were mixed in DCM (4 mL), and the evaporated solution was added. The mixture was stirred at 0°C for 5 min and heated at 50°C for 2 h. After cooling to room temperature, the reaction mixture was extracted with ethyl acetate and washed with brine. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography to give the product (146 mg, 39%).

[0140] R f (n-hexane / EtOAc, 80:20) = 0.61; pale yellow solid.

[0141] 1 H NMR (300 MHz, CDCl3): 7.46 - 7.11 (m, 11H), 7.07 (d, J = 7.9 Hz, 2H), 6.78 - 6.62 (m, 2H), 6.19 (s, 1H), 5.65 (s, 1H), 5.35 (s, 1H), 4.42 (t, J = 7.7 Hz, 1H), 4.21 - 4.00 (m, 2H), 2.32 (s, 3H). - 13C NMR (101 MHz, CDCl3): 149.14, 145.68, 144.65, 142.47, 141.60, 131.29, 129.68, 128.65, 128.30, 126.70, 121.24, 114.44, 111.46, 50.35, 45.41, 20.90.

[0142]

[0143] (Z)-N-phenethyl-N'-(p-tolyl)furan-2-carboximidamide (K24)

[0144] A solution of N-(p-toyl)furan-2-carboxamide (155 mg, 0.771 mmol) in SOCl2 (1.5 mL) was stirred at 80°C for 6 h. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was dissolved in toluene (1.5 mL), and the mixture was evaporated again. Phenethylamine (0.195 mL, 1.54 mmol) and TEA (0.321 mL, 2.31 mmol) were mixed in DCM (3 mL), and the evaporated solution was added. The mixture was stirred at 0°C for 5 min and heated at 50°C for 2 h. After cooling to room temperature, the reaction mixture was extracted with ethyl acetate and washed with brine. The organic layer was dried over anhydrous Na2SO4, filtered, and condensed. The residue was purified by silica gel column chromatography to give the product (103 mg, 44%).

[0145] R f (n-hexane / EtOAc, 80:20) = 0.51; yellow oil.

[0146] 1 H NMR (300 MHz, CDCl3): 7.38 - 7.16 (m, 8H), 7.06 (d, J = 7.9 Hz, 2H), 6.73 (d, J = 7.9 Hz, 2H), 6.25 (s, 1H), 3.76 (t, J = 7.0 Hz, 2H), 3.01 (t, J = 7.0 Hz, 2H), 2.32 (s, 3H). - 13C NMR (101 MHz, CDCl3): 149.83, 146.17, 145.70, 143.42, 140.47, 130.10, 129.68, 129.15, 128.74, 126.42, 121.56, 113.80, 111.68, 42.69, 34.99, 20.89.

[0147]

[0148] (Z)-N-phenethyl-N'-phenylthiophene-2-carboximidamide (K101)

[0149] A solution of N-phenylthiophene-3-carboxamide (150 mg, 0.738 mmol) in SOCl2 (1.5 mL) was stirred at 80°C for 6 h. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was dissolved in toluene (1.5 mL), and the mixture was evaporated again. Phenethylamine (0.186 mL, 1.48 mmol) and TEA (0.307 mL, 2.21 mmol) were mixed in DCM (2.5 mL), and the evaporated solution was added. The mixture was stirred at 0°C for 5 min, heated at 50°C for 2 h, filtered, and concentrated. After cooling to room temperature, the reaction mixture was extracted with DCM and washed with brine. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography to give the product (69 mg, 31%).

[0150] R f (n-hexane / EtOAc, 80:20) = 0.40; yellow oil.

[0151] 1 H NMR (300 MHz, CDCl3) δ7.55 (dd, J = 5.0, 1.2 Hz, 1H), 7.34 - 7.22 (m, 5H), 7.14 (t, J = 7.6 Hz, 5H), 7.02 - 6.95 (m, 1H), 6.88 - 6.81 (m, 2H), 6.78 (s, 1H), 3.64 (q, J = 6.9 Hz, 2H), 2.98 (t, J = 6.9 Hz, 2H).

[0152]

[0153] (Z)-N-(2,2-diphenylethyl)-N'-phenylthiophene-2-carboximidamide (K102)

[0154] A solution of N-phenylthiophene-3-carboxamide (150 mg, 0.738 mmol) in SOCl2 (1.5 mL) was stirred at 80°C for 6 h. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was dissolved in toluene (1.5 mL), and the mixture was evaporated again. 2,2-diphenylethylamine (250 mg, 1.48 mmol) and TEA (0.307 mL, 2.21 mmol) were mixed in DCM (2.5 mL), and the evaporated solution was added. The mixture was stirred at 0°C for 5 min and heated at 50°C for 2 h. After cooling to room temperature, the reaction mixture was extracted with DCM and washed with brine. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography to give the product (71 mg, 25%).

[0155] R f (n-hexane / EtOAc, 80:20) = 0.43; pale yellow solid.

[0156] 1 H NMR (300 MHz, CDCl3) δ7.45 - 7.10 (m, 14H), 6.93 (t, J = 7.3 Hz, 1H), 6.85 - 6.67 (m, 4H), 4.64 (s, 1H), 4.46 (t, J = 7.8 Hz, 1H), 4.15 (dd, J = 7.8, 3.8 Hz, 2H).

[0157]

[0158] (Z)-N-phenethyl-N'-(p-tolyl)thiophene-2-carboximidamide (K103)

[0159] A solution of N-(p-tolyl)thiophene-2-carboxamide (150 mg, 0.690 mmol) in SOCl2 (1.5 mL) was stirred at 80°C for 6 h. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was dissolved in toluene (1.5 mL), and the mixture was evaporated again. Phenethylamine (0.174 mL, 1.38 mmol) and TEA (0.287 mL, 2.07 mmol) were mixed in DCM (2.5 mL), and the evaporated solution was added. The mixture was stirred at 0°C for 5 min and heated at 50°C for 2 h. After cooling to room temperature, the reaction mixture was extracted with DCM and washed with brine. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography to give the product (72 mg, 33%).

[0160] R f (n-hexane / EtOAc, 80:20) = 0.38; pale yellow oil.

[0161] 1 H NMR (300 MHz, CDCl3) δ7.55 (d, J = 5.0 Hz, 1H), 7.34 - 7.21 (m, 5H), 7.16 - 7.09 (m, 2H), 7.00 - 6.92 (m, 3H), 6.80 - 6.70 (m, 3H), 3.62 (q, J = 6.9 Hz, 2H), 2.97 (t, J = 6.9 Hz, 2H), 2.23 (s, 3H).

[0162]

[0163] (Z)-N-(2,2-diphenylethyl)-N'-(p-tolyl)thiophene-2-carboximidamide (K104)

[0164] A solution of N-(p-tolyl)thiophene-2-carboxamide (150 mg, 0.690 mmol) in SOCl2 (1.5 mL) was stirred at 80°C for 6 h. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was dissolved in toluene (1.5 mL), and the mixture was evaporated again. 2,2-diphenylethylamine (234 mg, 1.38 mmol) and TEA (0.287 mL, 2.07 mmol) were mixed in DCM (2.5 mL), and the evaporated solution was added. The mixture was stirred at 0°C for 5 min and heated at 50°C for 2 h. After cooling to room temperature, the reaction mixture was extracted with DCM and washed with brine. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography to give the product (74 mg, 27%).

[0165] R f (n-hexane / EtOAc, 80:20) = 0.45; pale yellow solid.

[0166] 1 H NMR (300 MHz, CDCl3): 7.36 - 7.27 (m, 7H), 7.26 - 7.11 (m, 4H), 6.99 - 6.92 (m, 2H), 6.85 - 6.68 (m, 2H), 6.61 (d, J = 7.8 Hz, 2H), 4.60 (s, 1H), 4.45 (t, J = 7.7 Hz, 1H), 4.12 (d, J = 7.7 Hz, 2H), 2.26 (s, 3H).

[0167]

[0168] (Z)-N-(2,2-diphenylethyl)-N'-phenylthiophene-3-carboximidamide (K105)

[0169] A solution of N-phenylthiophene-3-carboxamide (200 mg, 0.984 mmol) in SOCl2 (2.0 mL) was stirred at 80°C for 6 h. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was dissolved in toluene (2.0 mL), and the mixture was evaporated again. 2,2-diphenylethylamine (333 mg, 1.97 mmol) and TEA (0.409 mL, 2.95 mmol) were mixed in DCM (4.0 mL), and the evaporated solution was added. The mixture was stirred at 0°C for 5 min and heated at 50°C for 2 h. After cooling to room temperature, the reaction mixture was extracted with DCM and washed with brine. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography to give the product (36 mg, 10%).

[0170] R f (n-hexane / EtOAc, 80:20) = 0.33; white solid.

[0171] 1 H NMR (300 MHz, CDCl3) δ7.37 - 7.18 (m, 11H), 7.17 - 6.97 (m, 4H), 6.87 (t, J = 7.3 Hz, 1H), 6.70 - 6.63 (m, 2H), 6.56 (d, J = 4.8 Hz, 1H), 4.57 (s, 1H), 4.46 (t, J = 7.9 Hz, 1H), 4.13 (d, J = 7.9 Hz, 2H).

[0172]

[0173] (Z)-N-phenethyl-N'-(p-tolyl)thiophene-3-carboximidamide (K106)

[0174] A solution of N-(p-tolyl)thiophene-3-carboxamide (200 mg, 0.737 mmol) in SOCl2 (2.0 mL) was stirred at 80°C for 6 h. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was dissolved in toluene (2.0 mL), and the mixture was evaporated again. Phenethylamine (0.186 mL, 1.47 mmol) and TEA (0.307 mL, 2.21 mmol) were mixed in DCM (4.0 mL), and the evaporated solution was added. The mixture was stirred at 0°C for 5 min and heated at 50°C for 2 h. After cooling to room temperature, the reaction mixture was extracted with DCM and washed with brine. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography to give the product (149 mg, 63%).

[0175] R f (n-hexane / EtOAc, 80:20) = 0.26; yellow oil.

[0176] 1 H NMR (300 MHz, CDCl3): 7.37 - 7.21 (m, 7H), 7.19 - 7.15 (m, 1H), 7.10 - 7.04 (m, 1H), 6.91 (d, J = 7.8 Hz, 2H), 6.67 (d, J = 5.2 Hz, 1H), 6.57 (d, J = 7.8 Hz, 2H), 4.56 (s, 1H), 3.75 (t, J = 6.8 Hz, 2H), 3.01 (t, J = 6.8 Hz, 2H), 2.23 (s, 3H).

[0177]

[0178] (Z)-N-(2,2-diphenylethyl)-N'-(p-tolyl)thiophene-3-carboximidamide (K107)

[0179] A solution of N-(p-tolyl)thiophene-3-carboxamide (200 mg, 0.737 mmol) in SOCl2 (2.0 mL) was stirred at 80°C for 6 h. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was dissolved in toluene (2.0 mL), and the mixture was evaporated again. 2,2-diphenylethylamine (250 mg, 1.47 mmol) and TEA (0.307 mL, 2.21 mmol) were mixed in DCM (4.0 mL), and the evaporated solution was added. The mixture was stirred at 0°C for 5 min and heated at 50°C for 2 h. After cooling to room temperature, the reaction mixture was extracted with DCM and washed with brine. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography to give the product (80 mg, 27%).

[0180] R f (n-hexane / EtOAc, 80:20) = 0.28; white solid.

[0181] 1 H NMR (300 MHz, CDCl3): 7.40 - 7.22 (m, 12H), 7.04 (q, J = 3.7 Hz, 2H), 6.94 (d, J = 7.9 Hz, 2H), 6.63 - 6.55 (m, 3H), 4.54 (s, 1H), 4.48 (t, J = 7.5 Hz, 1H), 4.15 (d, J = 7.5 Hz, 2H), 2.26 (s, 3H).

[0182]

[0183] (Z)-N-phenethyl-N'-phenylfuran-3-carboximidamide (K108)

[0184] A solution of N-phenylfuran-3-carboxamide (200 mg, 1.07 mmol) in SOCl2 (2.0 mL) was stirred at 80°C for 6 h. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was dissolved in toluene (2.0 mL), and the mixture was evaporated again. Phenethylamine (0.270 mL, 2.14 mmol) and TEA (0.444 mL, 3.21 mmol) were mixed in DCM (4.0 mL), and the evaporated solution was added. The mixture was stirred at 0°C for 5 min and heated at 50°C for 2 h. After cooling to room temperature, the reaction mixture was extracted with DCM and washed with brine. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography to give the product (150 mg, 48%).

[0185] R f (n-hexane / EtOAc, 80:20) = 0.41; pale pink solid.

[0186] 1 H NMR (300 MHz, CDCl3): 7.40 - 7.10 (m, 10H), 6.93 (t, J = 7.4 Hz, 1H), 6.74 (d, J = 7.7 Hz, 2H), 5.94 (s, 1H), 4.52 (s, 1H), 3.73 (t, J = 6.7 Hz, 2H), 2.99 (t, J = 6.7 Hz, 2H).

[0187]

[0188] (Z)-N-(2,2-diphenylethyl)-N'-phenylfuran-3-carboximidamide (K109)

[0189] A solution of N-phenylfuran-3-carboxamide (200 mg, 1.07 mmol) in SOCl2 (2.0 mL) was stirred at 80°C for 6 h. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was dissolved in toluene (2.0 mL), and the mixture was evaporated again. 2,2-diphenylethylamine (362 mg, 2.14 mmol) and TEA (0.444 mL, 3.21 mmol) were mixed in DCM (4.0 mL), and the evaporated solution was added. The mixture was stirred at 0°C for 5 min and heated at 50°C for 2 h. After cooling to room temperature, the reaction mixture was extracted with DCM and washed with brine. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography to give the product (246 mg, 63%).

[0190] R f (n-hexane / EtOAc, 80:20) = 0.58; pale pink solid.

[0191] 1 H NMR (300 MHz, CDCl3): 7.37 - 7.11 (m, 16H), 7.05 (s, 1H), 6.95 - 6.89 (m, 1H), 6.73 (d, J = 7.7 Hz, 2H), 5.83 (d, J = 1.9 Hz, 1H), 4.43 (t, J = 8.0 Hz, 2H), 4.17 - 4.04 (m, 2H).

[0192]

[0193] (Z)-N-phenethyl-N'-(p-tolyl)furan-3-carboximidamide (K110)

[0194] A solution of N-(p-tolyl)furan-3-carboxamide (200 mg, 0.994 mmol) in SOCl2 (2.0 mL) was stirred at 80°C for 6 h. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was dissolved in toluene (2.0 mL), and the mixture was evaporated again. Phenethylamine (0.251 mL, 1.99 mmol) and TEA (0.413 mL, 2.98 mmol) were mixed in DCM (4.0 mL), and the evaporated solution was added. The mixture was stirred at 0°C for 5 min and heated at 50°C for 2 h. After cooling to room temperature, the reaction mixture was extracted with DCM and washed with brine. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography to give the product (209 mg, 69%).

[0195] R f (n-hexane / EtOAc, 80:20) = 0.33; light pink solid.

[0196] 1 H NMR (300 MHz, CDCl3) δ7.36 - 7.14 (m, 8H), 6.97 (d, J = 7.8 Hz, 2H), 6.63 (d, J = 7.8 Hz, 2H), 5.95 (s, 1H), 4.48 (s, 1H), 3.71 (t, J = 6.8 Hz, 2H), 2.98 (t, J = 6.8 Hz, 2H), 2.26 (s, 3H).

[0197]

[0198] (Z)-N-(2,2-diphenylethyl)-N'-(p-tolyl)furan-3-carboximidamide (K111)

[0199] A solution of N-(p-tolyl)furan-3-carboxamide (200 mg, 0.994 mmol) in SOCl2 (2.0 mL) was stirred at 80°C for 6 h. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was dissolved in toluene (2.0 mL), and the mixture was evaporated again. 2,2-diphenylethylamine (336 mg, 1.99 mmol) and TEA (0.413 mL, 2.98 mmol) were mixed in DCM (4.0 mL), and the evaporated solution was added. The mixture was stirred at 0°C for 5 min and heated at 50°C for 2 h. After cooling to room temperature, the reaction mixture was extracted with DCM and washed with brine. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography to give the product (243 mg, 64%).

[0200] R f (n-hexane / EtOAc, 80:20) = 0.54; pale orange solid.

[0201] 1 H NMR (300 MHz, CDCl3) δ7.36 - 7.17 (m, 10H), 7.12 (t, J = 1.7 Hz, 1H), 7.05 (s, 1H), 6.97 (d, J = 7.8 Hz, 2H), 6.62 (d, J = 7.8 Hz, 2H), 5.89 - 5.80 (m, 1H), 4.42 (t, J = 7.9 Hz, 2H), 4.09 (d, J = 7.9 Hz, 2H), 2.26 (s, 3H).

[0202]

[0203] Experimental Example 1. In vitro IDO1 inhibition assay

[0204] To measure the enzyme inhibition activity of purified IDO1 protein, the amount of the reaction product N-formylkynurenine was measured at the absorbance Ex / Em = 400 / 500 nm after the reaction including purified recombinant IDO1 protein, D-Tryptophan substrate, and compounds. Holo-IDO1 protein at a concentration of 10 nM and compounds serially diluted to 2-fold concentrations were mixed in a working buffer composition [50 mM potassium phosphate buffer (pH 6.5), 0.01% Tween 20 (v / v)] with a concentration of 1% DMSO, and incubated at 37°C for 2 hours. Then, 2 mM D-Trp was mixed in a double concentration of assay buffer [10 mM ascorbic acid, 10 μM methylene blue, 0.25% catalase], and the reaction was performed at 37°C for 1 hour. 500 mM piperidine, an N-formylkynurenine-derived fluorophore, was added, and the amount of product N-formylkynurenine was measured at Ex / Em = 400 / 500 nm after a 20-minute reaction at 65°C.

[0205]

[0206] Experimental Example 2. Cell-based IDO1 inhibition assay using HeLa cells

[0207] HeLa 20,000 cells were prepared in a well, and incubated with compounds at appropriate concentrations at 37°C for 2 hours. Human Interferon gamma provided by the Kynurenine ELISA kit (#MBS495082, MyBioSource Inc., USA) was added, and incubated at 37°C for 18 hours. After washing three times with wash buffer, the cells were reacted with enzyme-conjugate for 30 minutes at 25°C, washed four times with wash buffer, and incubated with L-tryptophan substrate for 30 minutes at 25°C. The reaction was terminated with stop-solution, and the amount of kynurenine was calculated by measuring the absorbance at 450 nm.

[0208]

[0209] The results of Examples 1 and 2 are shown in Table 1 below.

[0210] Cell based assayIn vitroassay (IDO1)% inhibition (10 μM)% inhibition (5 μM)K1583.023.1K1972.013.3K2386.015.1K2480.08.9K1019.210.0*K10233.421.6*K10316.812.0*K10413.4 18.8*K1052.124.4*K10615.016.8*K10737.423.1*K1082.712.8*K10913.820.3*K1107.212.7*K11124.422.3*

[0211] * % inhibition (10 μM)

[0212] The above description is merely illustrative of the present invention, and those skilled in the art will appreciate that various modifications may be made without departing from the essential characteristics of the present invention. Therefore, the embodiments disclosed in this specification are intended to illustrate, not limit, the present invention, and the spirit and scope of the present invention are not limited by these embodiments. The scope of protection of the present invention should be interpreted by the following claims, and all techniques within a scope equivalent thereto should be interpreted as being included within the scope of the present invention.

[0213] The compound of the present invention has an effect of inducing apoptosis of cancer cells through inhibition of indoleamine 2,3-dioxygenase 1 (IDO1) and / or indoleamine 2,3-dioxygenase 2 (IDO2), and thus can be used in anticancer drugs and in foods for preventing, improving, and treating cancer.

Claims

1. A compound represented by the following chemical formula 1, a stereoisomer, tautomer, derivative, hydrate, solvate or pharmaceutically acceptable salt thereof Chemical Formula 1 {In the above chemical formula 1, X is O or S, L is C1~C 30 alkylene group; C2~C 30 alkenylene group of; or C2~C 30 is selected from the group consisting of alkynylene groups; Ar 1 and Ar 2 are independently C6~C 30 Aryl group of; C2~C containing at least one heteroatom of N, O or S 30 Heterocyclic group of; and C3~C 30 is selected from the group consisting of aliphatic rings; Here, the above alkyl group, alkenyl group, alkynyl group, aryl group, heterocyclic group and aliphatic ring group are each halogen; cyano group; hydroxy group; nitro group; amino group; acetoxy group; C1~C 20 Alkyl group of; C2~C 20 Alkenyl group of; C2~C 20 Alkynyl group of; C1~C 20 Alkoxy group of; C6~C 20 Aryl group of; C6~C 20 Aryloxy group of; C7~C 20 Arylalkyl group of; C1~C 20 Alkyl ester group of; C2~C containing at least one heteroatom of N, O or S 20 Heterocyclic group of; and C3~C 20 may be further substituted with one or more substituents selected from the group consisting of an aliphatic ring group; 2. In paragraph 1, L is C1~C 30 A compound characterized by an alkylene group, a stereoisomer, a tautomer, a derivative, a hydrate, a solvate or a pharmaceutically acceptable salt thereof 3. In the first paragraph, the Ar 1 and Ar 2 are independently of each other C1~C 20 C6~C substituted or unsubstituted with an alkyl group 30 A compound characterized by an aryl group, a stereoisomer thereof, a tautomer, a derivative, a hydrate, a solvate or a pharmaceutically acceptable salt thereof 4. In the first paragraph, the chemical formula 1 is a compound characterized by being represented by the following chemical formula 1-1 or chemical formula 1-2, a stereoisomer thereof, a tautomer, a derivative, a hydrate, a solvate or a pharmaceutically acceptable salt thereof. Chemical Formula 1-1 Chemical Formula 1-2 {In the above chemical formula 1-1 and chemical formula 1-2, X, L, Ar 1 and Ar 2 is the same as defined in claim 1 above.} 5. In the first paragraph, the chemical formula 1 is a compound characterized by being represented by the following chemical formula 1-3, a stereoisomer thereof, a tautomer, a derivative, a hydrate, a solvate or a pharmaceutically acceptable salt thereof. Chemical Formula 1-3 {In the above chemical formula 1-3, X, L and Ar 2 is the same as defined in claim 1 above, R 1 are independently the same or different from each other, hydrogen; deuterium; halogen; cyano group; hydroxyl group; nitro group; amino group; acetoxy group; C1~C 20 Alkyl group of; C2~C 20 Alkenyl group of; C2~C 20 Alkynyl group of; C1~C 20 Alkoxy group of; C6~C 20 Aryl group of; C6~C 20 Aryloxy group of; C7~C 20 Arylalkyl group of; C1~C 20 Alkyl ester group of; C2~C containing at least one heteroatom of N, O or S 20 Heterocyclic group of; and C3~C 20 is selected from the group consisting of aliphatic rings; a is an integer from 0 to 5.} 6. In the first paragraph, the chemical formula 1 is a compound characterized by being represented by the following chemical formula 1-4, a stereoisomer thereof, a tautomer, a derivative, a hydrate, a solvate or a pharmaceutically acceptable salt thereof. Chemical Formula 1-4 {In the above chemical formula 1-4, X and Ar 1 is the same as defined in claim 1 above, R 2 are independently the same or different from each other, hydrogen; deuterium; halogen; cyano group; hydroxyl group; nitro group; amino group; acetoxy group; C1~C 20 Alkyl group of; C2~C 20 Alkenyl group of; C2~C 20 Alkynyl group of; C1~C 20 Alkoxy group of; C6~C 20 Aryl group of; C6~C 20 Aryloxy group of; C7~C 20 Arylalkyl group of; C1~C 20 Alkyl ester group of; C2~C containing at least one heteroatom of N, O or S 20 Heterocyclic group of; and C3~C 20 is selected from the group consisting of aliphatic rings; R 3 is hydrogen; or C6~C 20 aryl group of; b is an integer from 0 to 5.} 7. In the first paragraph, the chemical formula 1 is a compound characterized by being represented by the following chemical formula 1-5, a stereoisomer thereof, a tautomer, a derivative, a hydrate, a solvate or a pharmaceutically acceptable salt thereof. Chemical Formula 1-5 {In the above chemical formula 1-5, X is as defined in claim 1 above, R 1 and R 2 are independently the same or different from each other, and independently hydrogen; deuterium; halogen; cyano group; hydroxyl group; nitro group; amino group; acetoxy group; C1~C 20 Alkyl group of; C2~C 20 Alkenyl group of; C2~C 20 Alkynyl group of; C1~C 20 Alkoxy group of; C6~C 20 Aryl group of; C6~C 20 Aryloxy group of; C7~C 20 Arylalkyl group of; C1~C 20 Alkyl ester group of; C2~C containing at least one heteroatom of N, O or S 20 Heterocyclic group of; and C3~C 20 is selected from the group consisting of aliphatic rings; R 3 is hydrogen; or C6~C 20 aryl group of; a and b are integers from 0 to 5, independently of each other.

8. In the first paragraph, the chemical formula 1 is a compound characterized by being represented by any one of the following compounds, a stereoisomer thereof, a tautomer, a derivative, a hydrate, a solvate thereof, or a pharmaceutically acceptable salt thereof.

9. An anticancer pharmaceutical composition comprising a compound according to paragraph 1, a stereoisomer, tautomer, derivative, hydrate, solvate or pharmaceutically acceptable salt thereof as an active ingredient.

10. In the 9th paragraph, the composition is used for treating brain cancer, neuroendocrine cancer, myeloma, lymphoma, leukemia, lymphangioendotheliosarcoma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, glioma, meningioma, neuroblastoma, EMC (extraskeletal myxoid chondrosarcoma), gastric cancer, lung cancer, breast cancer, ovarian cancer, liver cancer, bronchial cancer, nasopharyngeal cancer, laryngeal cancer, pancreatic cancer, bladder cancer, adrenal cancer, colon cancer, colon cancer, cervical cancer, prostate cancer, bone cancer, skin cancer, thyroid cancer, parathyroid cancer, ureter cancer, testicular tumor, lung carcinoma, small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, colon adenocarcinoma, prostate carcinoma, squamous cell carcinoma, basal cell carcinoma, An anticancer pharmaceutical composition characterized in that it targets at least one disease selected from the group consisting of adenocarcinoma, renal cell carcinoma, hepatocellular carcinoma, biliary tract cancer, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteosarcoma, chordoma, hemangiosarcoma, endotheliosarcoma, lymphangiosarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, rhabdomyomas, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, bulbar thyroid carcinoma, bronchial carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilm's tumor, Kaposi's sarcoma, and retinoblastoma.

11. In claim 9, the composition is an anticancer pharmaceutical composition characterized in that it induces apoptosis of cancer cells through inhibition of indoleamine 2,3-dioxygenase 1 (IDO1) or indoleamine 2,3-dioxygenase 2 (IDO2).

12. A method for treating cancer in a mammal, comprising administering a composition according to any one of claims 9 to 11.

13. Use of a compound of any one of claims 1 to 8, a stereoisomer, tautomer, derivative, hydrate, solvate or pharmaceutically acceptable salt thereof for the manufacture of a drug for preventing or treating cancer.

Images